We have identified what we believe is the first small molecule that down-regulates c-MYC. We have compelling evidence that it is the interaction between TMPyP4 and the NHE III and the associated proteins involved in transcriptional activation that leads to down-regulation of c-MYC expression. In this project we propose to exploit the capability to down-regulate c-MYC with cationic porphyrins to treat patients who have, either pancreatic or colorectal cancer. We will use in vitro and in vivo models to predict the best opportunities for therapeutic intervention using the optimum drug treatment protocols. In a parallel effort, supported by an RO1 grant, the mechanistic aspects of c-MYC down-regulation will be explored. Cytermex, Inc., a biotechnology start-up company, is involved in the optimization of cationic porphyrins for down-regulation of c-MYC, will supply the optimized cationic porphyrins for testing, and will also sponsor the preclinical pharmacology and toxicology. After completion of the in vitro and in vivo studies and selection of a lead compound, an IND will be filed and a phase I clinical trial conducted. Pancreatic and colorectal cancers have a mortality rate of 29,500 and 56,700, respectively, and we would expect an effective agent that down-regulates c-MYC to have a significant impact on both of these diseases.